The increasing incidence of obesity-linked type 2 diabetes in the US represents a major health problem. The adipocyte-derived hormone leptin regulates energy balance via a specific leptin receptor. In rodents, mutations in leptin or its receptor result in profound obesity. While such mutations in humans are rare, other molecular defects in leptin function may play a role in human obesity and type II diabetes. Knowledge of the normal mechanisms of leptin signaling will enable us to understand mechanisms of leptin dysregulation in disease states. Several leptin receptor forms engage the Jak2 tyrosine kinase. This proposal, Molecular determinants of leptin receptor/Jak2 signaling, explores the mechanisms by which the leptin receptor and Jak2 associate, mechanisms of intracellular signal generation by the leptin receptor, and how these signals contribute to leptin action at a cellular level. The specific aims focus on three areas: 1. Leptin receptor/Jak kinase interactions. 2. Tyrosine phosphorylation of the leptin receptor in leptin signaling. 3. Tyrosine phosphorylation of Jak2 in leptin signaling. The detailed molecular understanding of the mechanisms by which leptin mediates intracellular signals will help to elucidate the pathophysiology of -- and may enable the rational design of therapies for -- obesity and its attendant morbidities, including type 2 diabetes.